Interactive comorbidity between opioid drug abuse and HIV-1 Tat

Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons

Sylvia Fitting, Ruqiang Xu, Cecilia Bull, Shreya K. Buch, Nazira El-Hage, Avindra Nath, Pamela E. Knapp, Kurt F. Hauser

Research output: Contribution to journalArticle

Abstract

HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering μ and κ, but not δ, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ± morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.

Original languageEnglish (US)
Pages (from-to)1397-1410
Number of pages14
JournalAmerican Journal of Pathology
Volume177
Issue number3
DOIs
StatePublished - Sep 2010

Fingerprint

Corpus Striatum
Morphine
Opioid Analgesics
Substance-Related Disorders
HIV-1
Comorbidity
Spine
Pathology
Neurons
Doxycycline
HIV Infections
Pro-Opiomelanocortin
Dendritic Spines
Neuronal Plasticity
Opportunistic Infections
Opioid Receptors
Transgenic Mice
Hippocampus
Central Nervous System
HIV

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Interactive comorbidity between opioid drug abuse and HIV-1 Tat : Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. / Fitting, Sylvia; Xu, Ruqiang; Bull, Cecilia; Buch, Shreya K.; El-Hage, Nazira; Nath, Avindra; Knapp, Pamela E.; Hauser, Kurt F.

In: American Journal of Pathology, Vol. 177, No. 3, 09.2010, p. 1397-1410.

Research output: Contribution to journalArticle

Fitting, Sylvia ; Xu, Ruqiang ; Bull, Cecilia ; Buch, Shreya K. ; El-Hage, Nazira ; Nath, Avindra ; Knapp, Pamela E. ; Hauser, Kurt F. / Interactive comorbidity between opioid drug abuse and HIV-1 Tat : Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons. In: American Journal of Pathology. 2010 ; Vol. 177, No. 3. pp. 1397-1410.
@article{3c11749b4d6d4b0e96115b06f427333a,
title = "Interactive comorbidity between opioid drug abuse and HIV-1 Tat: Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons",
abstract = "HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering μ and κ, but not δ, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ± morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.",
author = "Sylvia Fitting and Ruqiang Xu and Cecilia Bull and Buch, {Shreya K.} and Nazira El-Hage and Avindra Nath and Knapp, {Pamela E.} and Hauser, {Kurt F.}",
year = "2010",
month = "9",
doi = "10.2353/ajpath.2010.090945",
language = "English (US)",
volume = "177",
pages = "1397--1410",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - Interactive comorbidity between opioid drug abuse and HIV-1 Tat

T2 - Chronic exposure augments spine loss and sublethal dendritic pathology in striatal neurons

AU - Fitting, Sylvia

AU - Xu, Ruqiang

AU - Bull, Cecilia

AU - Buch, Shreya K.

AU - El-Hage, Nazira

AU - Nath, Avindra

AU - Knapp, Pamela E.

AU - Hauser, Kurt F.

PY - 2010/9

Y1 - 2010/9

N2 - HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering μ and κ, but not δ, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ± morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.

AB - HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering μ and κ, but not δ, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ± morphine exposure underlie key aspects of chronic neurodegenerative changes in neuroAIDS, which may contribute to the exacerbated neurological impairment in HIV patients who abuse opioids.

UR - http://www.scopus.com/inward/record.url?scp=77956544206&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77956544206&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2010.090945

DO - 10.2353/ajpath.2010.090945

M3 - Article

VL - 177

SP - 1397

EP - 1410

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 3

ER -